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Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11...

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Autores principales: Nallanthighal, Sameera, Rada, Miran, Heiserman, James Patrick, Cha, Jennifer, Sage, Jessica, Zhou, Bo, Yang, Wei, Hu, Ye, Korgaonkar, Chaitali, Hanos, Christina Terpsithea, Ashkavand, Zahra, Norman, Kenneth, Orsulic, Sandra, Cheon, Dong-Joo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171147/
https://www.ncbi.nlm.nih.gov/pubmed/32312965
http://dx.doi.org/10.1038/s41419-020-2442-z
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author Nallanthighal, Sameera
Rada, Miran
Heiserman, James Patrick
Cha, Jennifer
Sage, Jessica
Zhou, Bo
Yang, Wei
Hu, Ye
Korgaonkar, Chaitali
Hanos, Christina Terpsithea
Ashkavand, Zahra
Norman, Kenneth
Orsulic, Sandra
Cheon, Dong-Joo
author_facet Nallanthighal, Sameera
Rada, Miran
Heiserman, James Patrick
Cha, Jennifer
Sage, Jessica
Zhou, Bo
Yang, Wei
Hu, Ye
Korgaonkar, Chaitali
Hanos, Christina Terpsithea
Ashkavand, Zahra
Norman, Kenneth
Orsulic, Sandra
Cheon, Dong-Joo
author_sort Nallanthighal, Sameera
collection PubMed
description Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.
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spelling pubmed-71711472020-04-27 Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer Nallanthighal, Sameera Rada, Miran Heiserman, James Patrick Cha, Jennifer Sage, Jessica Zhou, Bo Yang, Wei Hu, Ye Korgaonkar, Chaitali Hanos, Christina Terpsithea Ashkavand, Zahra Norman, Kenneth Orsulic, Sandra Cheon, Dong-Joo Cell Death Dis Article Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1. Nature Publishing Group UK 2020-04-20 /pmc/articles/PMC7171147/ /pubmed/32312965 http://dx.doi.org/10.1038/s41419-020-2442-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nallanthighal, Sameera
Rada, Miran
Heiserman, James Patrick
Cha, Jennifer
Sage, Jessica
Zhou, Bo
Yang, Wei
Hu, Ye
Korgaonkar, Chaitali
Hanos, Christina Terpsithea
Ashkavand, Zahra
Norman, Kenneth
Orsulic, Sandra
Cheon, Dong-Joo
Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer
title Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer
title_full Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer
title_fullStr Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer
title_full_unstemmed Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer
title_short Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer
title_sort inhibition of collagen xi alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171147/
https://www.ncbi.nlm.nih.gov/pubmed/32312965
http://dx.doi.org/10.1038/s41419-020-2442-z
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